William P. Horan - US grants

[unreadable] DESCRIPTION (provided by applicant): Anhedonia, the diminished ability to experience pleasant emotions, is a common, treatment-resistant negative symptom of schizophrenia that is associated with the profound impairments in social functioning that characterize this disorder. Recent research has raised fundamental questions about the precise nature of this emotional disturbance. Informed by a neurobehavioral model of hedonic experience, this proposal examines the hypothesis that schizophrenia is characterized by impaired appetitive pleasure (derived from anticipating enjoyable experiences or "wanting") but intact consummatory pleasure (experienced while engaged in enjoyable activities or "liking"). Stabilized schizophrenia outpatients and healthy control subjects will complete self-report questionnaires of trait appetitive and consummatory pleasure, as well as two electrophysiological paradigms that have been used to probe these aspects of hedonic experience in the basic affective science literature. Appetitive pleasure will be assessed with an emotional anticipation paradigm to examine the hypothesis that schizophrenia patients will demonstrate less Stimulus-Preceding Negativity (SPN) than healthy controls during the anticipation of pleasant visual stimuli, but comparable levels of SPN during anticipation of neutral and unpleasant stimuli. Consummatory pleasure will be assessed using an affective picture-viewing paradigm to examine the hypothesis that schizophrenia patients will demonstrate P300 and late positive potentials that are comparable to controls during direct exposure to pleasant and neutral visual stimuli, but greater P300 and late positive potentials than controls during direct exposure to unpleasant stimuli. This initial study will provide the groundwork for conducting more comprehensive evaluations of the neurophysiological underpinnings of anhedonia and other negative symptoms in schizophrenia. Anhedonia and other negative symptoms are associated with the profound impairments in independent living, vocational functioning, and social relationships that characterize schizophrenia. The development of novel treatments for anhedonia are therefore of particular public health significance, but such efforts are currently hampered by an inadequate understanding of its precise nature and physiological mechanisms. The proposed research will help guide the development of more effective treatments by using electrophysiological methods to evaluate whether anhedonia in schizophrenia primarily reflects impairment in the appetitive or the consummatory component of hedonic experience. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Negative symptoms are distinct clinical features of schizophrenia that are major determinants of the poor community functioning and poor long-term outcome that characterize the disorder. However, they are only minimally responsive to available treatments and are a substantial burden for care-givers. To address this critical unmet treatment need, the NIMH recently sponsored a consensus development conference to identify research priorities to stimulate the development of novel treatments for negative symptoms. The number one recommendation for advancing research and moving towards new treatment development in this area was to develop a "next generation" assessment instrument that solves the conceptual and methodological problems of existing measures. For the instrument to achieve widespread acceptance, the conference participants concluded that it is essential to follow a transparent, rigorous scale development process using large, diverse, and representative samples. As members of the NIMH-MATRICS Negative Symptoms Workgroup, the Principal Investigators have collaborated with experts from academia, the pharmaceutical industry, and government agencies to develop a new instrument, the Negative Symptom Rating Scale (NSRS). The proposed four-site Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS), including the Universities of Maryland, Pennsylvania, California-Los Angeles, and California-Berkeley, is designed to carry out the recommendations of this NIMH initiative over a three-year period. These four sites represent areas of ongoing research in schizophrenia and negative symptoms, with the necessary infrastructure and unique expertise to carry out the proposed studies. Study 1 will evaluate the psychometric properties of the beta version of the NSRS in 300 schizophrenia outpatients. Results will guide data-driven refinements of the instrument based on state-of-the-art data analytic techniques, including Item Response Theory analyses and item level factor analyses that will allow us to ascertain how well the NSRS items assesses the underlying negative symptom construct and its putative sub-components, the dimensional structure of the measure, and gender invariance. Study 2 will evaluate the psychometric properties, test-retest reliability, and factor structure via confirmatory factor analysis of the revised NSRS in160 patients with schizophrenia. Convergent/discriminant validity with respect to a range of other clinical and neurocognitive features of schizophrenia, as well as measures of social and emotional functioning will also be evaluated. The multi-site structure of the CANSAS will permit an efficient evaluation of the NSRS in large ethnically and clinically diverse samples, enabling us to rapidly disseminate a final version of the scale to researchers conducting clinical trials and other types of negative symptom research. PUBLIC HEALTH RELEVANCE: Negative symptoms are major determinants of poor functional outcome in schizophrenia and available treatments are largely ineffective for these symptoms. The proposed Collaboration to Advance Negative Symptom Assessment in Schizophrenia (CANSAS) will carry out the main recommendation of the recent NIMH Consensus Development Conference to create and validate a new assessment instrument, the Negative Symptom Rating Scale, for use in clinical trials and other types of research. This state-of-the art instrument will play a central role in the NIMH initiative to stimulate the development of new treatments aimed at reducing the disability associated with negative symptoms.

DESCRIPTION (provided by applicant): Schizophrenia (SCZ) and bipolar disorder-I (BPD) have many similarities, but they have notably different emotional response profiles to appetitive stimuli, and these are present even among clinically stable patients. The goal of this R21 application is to apply current affective neuroscience methods to understand the underlying processes for these different emotional response profiles. We will test hypotheses that stable outpatients with SCZ and euthymic BPD-I patients with a history of psychosis will demonstrate opposite central and peripheral nervous system responses to rewarding stimuli during two types of tasks: affective chronometry, which refers to the temporal parameters (e.g., anticipation, offset) of emotional responding, and motivational engagement, which refers to mobilization of physiological response systems during impending rewards and punishments. 35 SCZ outpatients, 35 euthymic BPD outpatients, and 35 matched healthy controls will complete the two types of paradigms while simultaneous ERP and startle eye blink responses are recorded. Affective chronometry will be measured with a passive emotional picture viewing task with startle probes before, during, and after picture presentation. Motivational engagement will be measured with an active motivational gradient task, in which cues signaling reward or punishment appear to loom progressively closer to the viewer. We predict SCZ patients will demonstrate hypo-reactivity and BPD patients will show hyper-reactivity for specific physiological responses to positive stimuli. Identification of emotional disturbances that are uniquely associated with SCZ and BPD would have direct implications for treatment development and identification of novel endophenotypes. PUBLIC HEALTH RELEVANCE: Schizophrenia (SCZ) and bipolar disorder-I (BPD) are two of the most severely disabling psychiatric disorders, and recent evidence suggests that notably different emotional response abnormalities contribute to poor outcome within each disorder. The goal of this R21 exploratory grant application is to apply affective neuroscience methods to test the hypothesis that stable outpatients with SCZ or BPD-I with a history of psychosis (in a euthymic mood state) will demonstrate differential central and peripheral nervous system responses during tasks that index affective chronometry and motivational engagement. Identification of emotional disturbances that are uniquely associated with each disorder would have direct implications for treatment development and novel emotional endophenotypes.

? DESCRIPTION (provided by applicant): Human beings have a fundamental need to belong. We are powerfully motivated to seek out, engage in, and maintain strong interpersonal attachments. Developing and maintaining close relationships, however, is not an easy task for many people with mental illnesses. Disturbances in social motivation are particularly debilitating, costly, and poorly understood in people with psychosis-related psychopathology (PRP). The RDoC affiliation construct provides a foundation for conceptualizing and unpacking the mechanisms of these disturbances in social motivation. Our scientific goal is to carve the RDoC affiliation construct into two separate sub-processes. Specifically, we will examine how the social approach and avoidance motivation systems of the brain relate to social disability across individuals with PRP and are impacted in their unaffected siblings. This project is grounded in a translational social neuroscience model of affiliation that includes two distinct neural sub-systems: (1) the social approach motivation system is sensitive to social safety signals and promotes social engagement and attachment (primarily involving the striatum, ventromedial frontal cortex, and hypothalamus); (2) the social avoidance motivation system is sensitive to social threat signals and promotes avoidance of rejection and discord (primarily involving the insula, anterior cingulate, and amygdala). These systems are modulated by select neuropeptides/transmitters, chiefly oxytocin (OXT), vasopressin (AVP), dopamine, and opioids. Data from our lab and others indicate that problems in affiliation can stem from disturbances in both of these systems across PRP. We predict that social approach and avoidance make independent contributions, though separable neurobehavioral mechanisms, to impaired social functioning in psychosis. In addition, we will evaluate these systems in unaffected siblings to determine whether they reflect vulnerability factors for social disability and psychosis (unconfounded by medication and chronicity). A diverse sample of 80 outpatients with a history of clinically significant psychotic symptoms, 80 of their unaffected siblings, and 40 healthy individuals from the community will complete established measures at four RDoC units of analysis: circuits (two social reward/punishment fMRI tasks), physiology (N170 responses to approving/ threatening faces), behavior (social reward/punishment learning task), and self-report (need for belonging, fear of rejection scales), as well as social functioning assessments. An exploratory aim will examine whether OXT/AVP molecule and receptor gene polymorphisms relate to individual differences across the four units of analysis. Our primary hypotheses test (1) the validity of the social approach and avoidance motivation constructs across multiple units of analyses and their predictive validity for explaining real world social functioning, and (2) whethe unaffected siblings show impairments in social approach/ avoidance that demonstrate significant within-family correlations. A mechanistic understanding of neural processes that lead to problems in social affiliation is essential for developing new recovery-oriented and preventative treatments.